Project Summary (Clinical Research Project: OMEGA2) Eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), and eosinophilic colitis (EC) are four distinct and rare diseases that have no FDA-approved treatments. These diseases are often collectively referred as eosinophilic gastrointestinal diseases (EGIDs). Our understanding of the pathogenesis of EGIDs has many gaps that include identification of predictors and biomarkers of longitudinal disease trajectory, understanding the molecular mechanisms and pathogenesis of these diseases, and defining relationships between transcriptional profiles and clinical phenotypes. The current standard of care (SOC) is repeated endoscopy with biopsy, and it is unclear whether biomarkers and patient-reported outcomes (PROs) can accurately function as surrogates for tissue histology. In the first cycle of the Consortium Eosinophilic Gastrointesinal Disease Researchers (CEGIR1), the longitudinal trial Outcome Measures for EGIDs across Ages (OMEGA1) filled important gaps in our knowledge. We identified relationships between PROs in children and their parents and the association of clinical outcome measures (COMs), including symptoms, endoscopy score, and quality of life (QOL) metrics, with histologic and molecular disease activity, focused on EoE. CEGIR elucidated distinct EoE endotypes and histologic and molecular commonalities and differences of EGIDs. In this second CEGIR cycle (CEGIR2), OMEGA2 proposes the overarching hypothesis that COMs and molecular biomarkers will associate with histologic features to allow accurate longitudinal phenotypic and clinical profiling of EGID patient populations. OMEGA2 will assess key issues for clinical trial readiness in EGIDs. Specifically, we aim to understand the COMs and transcriptome profiles that best reflect histologic disease courses to define and refine diagnostic criteria and outcome metrics for clinical trials. In Aim 1, we will determine the association between COMs and longitudinal disease courses. Using the existing and growing population of prospectively enrolled EGID patients, we will test the hypothesis that COMs, including PROs and endoscopic severity metrics, longitudinally correlate with histologic findings. We will determine whether COMs change over time and treatments and whether they correlate with EGID histology. In Aim 2, we will determine the association of EGID molecular profiles with phenotypes and outcomes. We will test the hypothesis that gastrointestinal mRNA transcript signatures longitudinally associate with clinical and histologic phenotypes, COMs, and treatment outcomes. We will determine whether diagnostic EG, EGE, and EC transcript panels predict treatment response and/or change with treatment. In Aim 3, we will establish diagnostic criteria and guidelines for EG, EGE, and EC using the COMs, endoscopic, histologic, and molecular data generated in OMEGA2 to conduct a formal consensus and guideline process. Collectively, we are proposing to further develop a longitudinal cohort of EGID patients that will answer fundamental questions concerning the natural history, disease definitions, and outcomes of these rare understudied diseases.